There is an urgent need for new modes of HIV therapy. Current therapies for HIV infection target the viral enzymes protease and reverse transcriptase. However, these therapies typically fail to control HIV long-term due to the transmission and emergence of multidrug-resistant variants, In addition, these treatments are associated with often intolerable side effects, and thus most HIV-infected individuals eventually exhaust their therapeutic options. HIV entry provides a promising target for a new generation of antiviral agents, and recent clinical trials have validated entry as a viable target for therapy. However, no orally available HIV entry inhibitor has entered advanced clinical testing. In the Phase I project, we performed ultra-high throughput screening of 4 million drug-like combinatorial compounds using a novel virus-free assay that accurately models all stages of HIV entry, Several active compounds were discovered, and the most promising compound was demonstrated to be a nontoxic and specific HIV inhibitor that acts at the level of membrane fusion, This novel compound derives from a promising lead series that possesses drug-like properties, facile chemistry and promising structure-activity relationships. The overall goal of this Phase II project is develop the lead series into a highly optimized compound that meets all criteria for human clinical testing as a new HIV therapy. The collaborative drug optimization program combines the medicinal and computational chemistry expertise of Pharmacopeia, Inc. with the antiviral and drug development expertise of Progenics Pharmaceuticals and our scientific collaborators at Albert Einstein College of Medicine. The project will employ an integrated and iterative process of synthesis and biological testing of more than 1000 compounds that are progressively optimized for antiviral potency, selectivity and drug-likeness. Additional studies wit1 establish the molecular determinants of HIV susceptibility to the compound. Lastly, the most highly optimized compounds will be tested for oral pharmacology and tolerability in animals in order to identify the agent that most warrants advancement into human clinical testing. Success in the Phase II project is defined as the development of a novel, orally available and well-tolerated compound that broadly inhibits HIV entry with nanomolar potency. Project success would lead to the preparation of clinical-grade material and regulatory documentation that would support human clinical testing of this new HIV therapy.